Project Summary The impetus for the proposed research is the need for strategies to improve the regeneration of orthopedic defects while concurrently mitigating the risk of infection. Synthetic bone substitutes offer an attractive alternative for the treatment of orthopedic fractures as compared to autologous bone grafts. However, these technologies still do not address infection related complications. Therefore, the objective of this research is to utilize a novel rapidly-degrading porogen to generate an interconnected pore structure within synthetic calcium phosphate cement. The fundamental hypothesis for this research project is that glucose based microparticles will degrade rapidly forming macropores within the constructs facilitating the ingrowth of bone while simultaneously improving the local delivery of clindamycin from Poly(D,L-lactic-co-glycolic-acid) microparticles (MPs). In order to accomplish the goals outlined in this project, two specific aims will be investigate. In the first specific aim, we will expand upon our preliminary in vitro results that suggest glucose microparticles can be successfully incorporated into calcium phosphate cements in order to generate macroporosity without sacrificing the clinical utility of these therapeutics. We will elucidate the upper limit for glucose/PLGA inclusion within CPCs by evaluating the effect of loading concentration on clinically relevant handling properties, evaluate the synergy between glucose and PLGA MPs on CPC degradation, the effect of glucose MPs on clindamycin release kinetics in vitro, and evaluate composite scaffolds biocompatibility with mesenchymal stem cells. The outcomes of this specific aim will reveal the important fabrication parameters for appropriate in vivo translation. In the second specific aim, we will investigate the effectiveness of a dual porogen CPC scaffold comprised of PLGA microparticles loaded with biologics and second-generation porogens for the treatment of orthopedic infections. Defects will be inoculated with Staphylococcus aureus, the most common pathogen associated with orthopedic fracture complications. A critical-sized infected femoral condyle defect will be inoculated with the pathogen. After 6 weeks, the femora will be evaluated for the volume of bone regenerated, the histological appearance of the regenerated bone, the mechanical properties. Upon completion of these studies we will have determined if a novel rapidly-degrading porogen can be utilized to enhance bone regeneration while simultaneously improving the efficacy of clindamycin release. Additionally, the training pan that my sponsor, co-sponsor and I have fabricated will aid in my long-term goal of becoming a physician scientist with in the field of orthopedic surgery.